In spite of numerous treatment options for patients with cancer, there remains a need for effective and safe therapeutic agents and a need for new combination therapies that can be administered for the effective long-term treatment of cancer.
Liver cancer or hepatic cancer is classified as primary liver cancer (i.e. cancer that forms in the tissues of the liver) and secondary liver cancer (i.e. cancer that spreads to the liver from another part of the body). According to the National Cancer Institute at the National Institutes of Health, the number of estimated new cases and deaths from liver and intrahepatic bile duct cancer in the United States in 2014 was 33,190 and 23,000, respectively. Importantly, the percent surviving five years or more after being diagnosed with liver and intrahepatic bile duct cancer is only about 16%.
It has now been found that a combination of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in free form or in pharmaceutically acceptable salt form and at least one further active ingredient, as defined herein, shows synergistic combination activity in an in vitro cell proliferation assay as shown in the experimental section and may therefore be effective for the delay of progression or treatment of a proliferative disease, such as cancer, in particular liver cancer.
Based on the synergistic combination activity shown in the experimental section, it would be expected that the combination of                (i) N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in free form or in pharmaceutically acceptable salt form and        (ii) at least one further active ingredient selected from the group consisting of                    a) 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea in free form or in pharmaceutically acceptable salt form;            b) 8-(6-amino-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrazin-2-yl)-8-azaspiro[4.5]decan-1-amine in free form or in pharmaceutically acceptable salt form;            c) 7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide in free form or in pharmaceutically acceptable salt form;            d) (S)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide in free form or in pharmaceutically acceptable salt form; and            e) 4-(trifluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine in free form or in pharmaceutically acceptable salt form,would result in an unexpected improvement in the treatment of proliferative diseases, particularly cancer, and more particularly liver cancer. This unexpected improvement would allow, for example, the reduction in the dose required for each compound, leading, for example, to a reduction in the side effects or an enhancement of the long-term clinical effectiveness of the compounds in treatment.                        
When administered simultaneously or sequentially, N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in free form or in pharmaceutically acceptable salt form, and at least one further active ingredient, as defined herein, interact in a synergistic manner to strongly inhibit cell proliferation and would be thus surprisingly efficacious in liver cancer. This unexpected synergistic reaction would allow, for example, reduction in the dose required for each compound, leading, for example, to a reduction in the side effects or an enhancement of the long-term clinical effectiveness of the compounds in treatment.